Pharmaceutical Validation

Aseptic Process validation--Media Fill operation in the sterile dry powder filling

2011-05-09T18:00:00.000-07:00

1.0 OBJECTIVE: To lay down a procedure for Media Fill operation in the sterile dry powder Filling facility..

2.0 RESPONSIBILTY

Microbiologist, Operator concerned/Production officer/QA Officer

3.0 ACCOUNTABILITY

Quality Control Manager/ Production Manager

4.0 PROCEDURE

PRE-START UP:

4.0 Ensure that all the equipments, HVAC system, water system and other utility services of the facility are validated.

4.1 Ensure that the Gamma irradiation certification report of the lactose + SCDM (Soyabean Casein Digest) mixture (3:1) from BARC and sterility test report (done in-house) is available.

4.2 Ensure that solubility test report and growth promotion/inhibition test report of sterile

lactose+SCDM mixture is available. [Solubility should be NLT 1gm/10 ml of WFI].

4.3 Ensure that solubility test report and growth promotion/inhibition test report of sterile lactose+SCDM mixture is available. [Solubility should be NLT 1gm/10 ml of WFI].

4.4 Ensure that freshly distilled WFI to be used for filling, is autoclaved and the sample given for sterility test.

4.5 Ensure that all the contact parts of Dry Powder Filling machine are duly cleaned and sterilized or sanitized.

4.6 Ensure that the last Environmental Control Reports of the area are conforming to the acceptance standard.

4.7 Ensure that the Liquid Filling machine is done inside the sterile filling area on the previous day after autoclaving /sanitization.

4.8 Ensure by manometer readings, that the pressure balancing of the sterile area is as per requirement.

4.9 Ensure that the cleaning, sanitization and fumigation of the area is done on the previous day.

START UP

4.9 Enter the sterile area as per SOP using gowns sterilized 4days back.

4.10 Check the cleanliness of the sterile area.

4.11 Check the cleanliness of the Liquid Filling machine.

4.12 Check and confirm the temperature and RH of liquid filling room is as per the requirement.

4.13 Assemble the Liquid Filling machine.Ensure that that filling of liquid and liquid can be done

simultaneously.

4.14 Measure the nonviable particulate count of filling cabinet and filling room.

OPERATION

4.15 Bring the autoclaved WFI container near the liquid filling assembly.

4.16 Transfer sterile SCDM liquid from the container in to liquid hopper.

4.17 Transfer sterile dried rubber stoppers (sterilized 4 days back) in to the hopper of stoppering unit. Send sample for sterility testing simultaneously.

4.18 Put the inlet suction tube of Liquid Filling Assembly into the WFI container.

4.19 Set the Liquid Filling machine for the respective dose.

4.20 Remove the Liquid Filling Assembly and all the contact parts. Disinfect it, clean it and get it sterilized/sanitised.

4.21 Ensure that all the left over rubber stoppers are given outside the sterile area for destruction.

4.22 Shut down the vial liquid-filling machine as per SOP

CLEANING:

4.23 Ensure that all the tools and accessories containers etc. used during media fill are given for cleaning/sanitization/sterilization.

4.24 Follow the cleaning and sanitization SOP for cleaning of sterile area.

4.25 Do the extra cleaning and sanitization of the floor/walls/machine after media fillrun with 10% Bacillocide and Lysol solution

ACCEPTANCE CRITERIA:

4.26 Initial validation: During initial validation, it should qualify all three consecutive media fill run i.e. during each run there should not be growth in more than two vials.

4.27 Revalidation: Only one media fill run in which there should not be any growth in more than two vials.

ELIGIBILITY CRITERIA FOR PERSONNEL PERFORMING MEDIA FILL RUN :

4.28 Persons involved in media fill should be medically examined and declared fit within last one year.

4.29 Persons should be trained on general hygiene and current gowning procedure, and the present health condition should be O.K.

4.30 The personnel should be microbiologically monitored during run.

NOTES

In case of any positive growth in any vial during the incubation period.\

4.31 It should be isolated and identified to the genus level.

4.32 If the isolated organism is other than the house flora, thorough investigation shall be carried out by Quality Assurance and Production.

4.33 The source of the contamination must be established.

In case of any failure in media fill run:

4.34 When there is no assignable cause, media fill shall be repeated three times and production should commence only after all the three runs meet the acceptance criteria.

4.35 When there is assignable cause, after rectification of the cause, repeat the media fill run once.

4.36 Before and during media fill run no special cleaning shall be carried out.

4.37 Normal production can resume only after minimum one day of environmental monitoring compliance report.

4.38 Batches filled before the final result of the media fill run shall not be released to the market till the media fill run passes in case of initial validation.

4.39 The routine environmental monitoring plates shall be kept for 14 days (in case of any growth) to help in investigation of any positive growth in the media filled vials.

4.40 If for any reason the media fill run is considered invalid vials shall not be incubated.

4.41 Media fill runs can be aborted for the same reason that a product lot would be aborted. All media filled units filled before an incident that would cause an aborted fill must be incubated.

4.42 During media fill all the Operators, Officers& Maintenance staff who are authorized to do the sterile filling, supervision and maintenance must be involved in media fill trial.

4.43 The volume of liquid filled must be sufficient to wet all surfaces including the closure and to facilitate inspection.

4.44 The line must be run at a slower speed than normal production run to give greater exposure time.

4.45 Total duration of the routine media fill must be the same or more as the longest process conducted on that line.

4.45 The incubation temperature of the filled containers must be sufficient to promote microbial growth at 30-35^oC. for 336hrs(stored upright) followed by 20-25^oC. for 336 hrs. (stored upside down).

4.47 Personnel that conduct the inspection of incubated media fills must have training on basic microbiological concepts ,concepts of media fill and examples of contaminated container showing various stages of growth.

POST MEDIA FILL RUN :

4.48 Filled incubated vials should be optically checked by microbiologist and certified.

4.49 Incubate the vial samples with no growth approximate 5 vials for 14 days with normal house flora and 5 vials with organisms used for the sterility test growth promotion for 14 days.

4.5 Temp. range for incubation 1^st two week at30 to 35^oC. (vials stored upright).

4.51 Next two week at 20 to 25^oC. (vials stored upside down).

4.52 These vials should show promotion of growth.

ANNEXURE - I

LIST OF PERMITTED INTERVENTIONS DURING FILLING

These are the activities which are performed during normal working in the sterile filling area:

1) Adjustment of weight in the dosing wheel.

2) Adjustment of Stopper holding spring.

3) Transfer of liquid from container to hopper.

4) Transfer of stoppers from bag to hopper.

5) Picking unstoppered vials from the outfeed back to conveyor for stoppering.

6) Adjustment of separator.

7) Picking up of fallen vials from turn table.

8) Cleaning of machine with vacuum cleaner.

9) Adjustment of stoppering channel height.

10) Adjustment of stoppering pressure rollers.

11) Replacing of a piston from the wheel.

12) Adjustment of turn table over load sensor.

13) Lifting and closing of the LAF cabinet door.

14) Checking the weight in balance.

15) Adjustment of dosing air.

16) Cleaning of vacuum pot.

17) Pushing stopper in the channel by forceps.

18) Power interruption (samples should be marked)

19) Number of personnel in sterile filling area (8 persons).

20) Multiple dosing of the liquid.

21) Running the machine at a slower speed than actual production run.

22) Covering the working shift usually 12 hours and shift Change over

23) Entry of maintenance person for repairing of M/C

ANNEXURE - III

ACCEPTANCE CRITERIA FOR MEDIA FILL SIMULATION

MAXIMUM NO.OF REJECTED VIALS ACCEPTABLE AT 95% CONFIDENCE LEVEL	PERCENTAGE OF FAILURE	BATCH SIZES
		5000	10000	20000	50000	100000	INFINITY
0	0.1%	2469	2668	2808	2912	2951	2995
1	0.1%	3676	4047	4339	4575	4670	4747
0*	0%	4684	5207	5670	6044	6207	6294*
0	0.01%				24698	26686	29944
1	0.01%				46093	47047	47047
2	0.01%					62911	62911
* Normal media fill run size

PROCESS VALIDATION PROTOCOL Autoclave

2011-02-07T09:43:00.000-08:00

1. PRE-EXECUTION APPROVAL

Successful completion of this protocol will provide documented evidence that all key aspects of the Autoclave used in LARGE VOLUME PARENTRALS SECTION adheres to appropriate application criteria, comply with standard operating procedures, and meet current Good Manufacturing Practices (cGMP) requirements.

1.1 SIGNATORY LIST

The signature below indicates approval of this protocol and its attachments for execution.

	Name & Designation	Signature	Date

Prepared By

Checked and Reviewed By

Approved By

1.2 Validation Team

All individuals participating in the execution of this protocol must fill out a row in the table below.

Name & Designation	Responsibility	Signature & Initial	Date

	Prepare the protocol and coordinate the validation study. Generate amendments to the protocol as required
	Microbiological validation of the sterilization process. document the microbiological aspects of the study
	Protocol training of operators and provide the resources for validation study

2.0 GLOSSARY OF TERMS

2.1 List of Abbreviation

CGMP Current Good Manufacturing Practices

FDA Food and Drug Administration

GAMP Good Automated Manufacturing Practice

GMP Good Manufacturing Practice

IQ Installation Qualification

OQ Operation Qualification

2.2 Definitions

Acceptance Criteria Agreed standards or ranges, which must be achieved.

Critical component A component within a system where the operation, contact, data, control, alarm, or failure may have a direct impact on the quality of the product.

Critical Instrument Any instrument that directly affects product safety, purity, or efficacy.

Direct Impact System An engineering system that may have a direct impact on product quality.

Factor Acceptance Test Documenting the performance characteristics of equipment prior to shipment to site.

Impact Assessment The process of evaluating the impact of the operating, controlling alarming and failure conditions of a system on the quality of a product.

Indirect Impact System An engineering system considered not having a direct impact on product quality.

Installation Qualification Documenting the process equipment and ancillary system are constructed and installed according to pre-determined specifications and functional requirements.

No Impact System This is a system that will not have any impact, either directly or indirectly, on product quality. These systems are designed and commissioned following Good engineering Practice only.

Non-critical Component A component within a system where the operation, contact, alarm or failure may have an indirect impact or no impact on the quality of product.

Operating Limits The minimum and /or maximum values that will ensure that product and safety requirements are met.

Operational Qualification Establishing confidence that process equipment and ancillary systems are capable of consistently operating within established limits and tolerances.

Performance Qualification The documented verification that al aspects of a facility, utility or equipment that can affect product quality perform as intended meeting pre-determined acceptance criteria.

Performance Testing The process by which the performance of interdependent system is demonstrated as within the required tolerances, the output of interdependent system is demonstrated as delivering the required duty or capacity, the interdependent functions of system are interdependent to be as specified and appropriate.

Piping and Instrumentation

Diagrams Primary source of design information for utility systems and process equipment. They are used to depict the process flow, equipment configuration, process parameters, instrumentation, and materials of construction. They also are used to perform overall material and energy balances and pressure balances.

3.0 INSTRUCTION

3.1. General Instruction

All performers and reviewers must complete qualification forms using the following guidelines:

· Complete all items on a form in full, except the optional comment’s section.

· Document any deviation from defined protocols and expected results. Owner approval of protocol deviations must be documented before final approval signatures can be obtained.

· Write additional comments on an addendum sheet when there is not enough space on a form to accommodate all comments. Use these three steps when adding an addendum sheet.

1. Number the page alphanumerically.

2. Initial and date additions.

3. Insert the addendum sheet behind the original page.

· Make all entries in permanent black or blue ball pen.

3.2 Correcting Entries

If you need to make corrections on a form, use the procedures described below:

3.2.1 Correcting Short Entries

To correct a short entry [such as a single word or test result] on a form:

1. Draw a diagonal line, bottom left to upper right, through the miss entered or incorrect information.

2. Write the correction to the upper right of the original entry.

3. Give brief explanation of change

4. Initial and date the change.

3.2.2 Correcting Long Entries

To correct a long entry or information block on a form:

1. Draw a diagonal line, bottom left to upper right, through the miss entered or incorrect information.

2. Write the correction on a separate addendum page.

3. Give brief explanation of change.

4. Initial and date the changes.

5. Number the page alphanumerically

6. Place the addendum page behind the original page.

3.3 Marking Elements That Are Not Applicable

Mark each element carefully according to the instruments below, so that it will be clear that the element is unnecessary and that you have not skipped or forgotten the element.

1. Draw a diagonal line, bottom left to upper right corner, through the element that is not required.

2. Write the letters NA [Not Applicable], your initials, and the date above the line. Include comments above the line or on the form to document the reason the element is not required.

3. Where NA is indicated as an option, select this field.

The performer and reviewer must sign and date all forms, as usual, even when part or all of the form is marked “NA”.

Note: All original entries must remain legible after any corrections have been made.

3.4 Caution

The following conditions require “re-qualification”;

· When a Instrument modification has been completed, it affects the installation qualification.

· When the software or firmware has been upgraded or changed

· When this Instrument is being removed from where it was originally installed.

3.5 Re-calibration / Re-certification Requirements

The following conditions require “re-calibration / re-certification;

· For a pre-determined period of time or use.

· After any minor service has been done or replacement of parts.

· When this Instrument is being removed from where it was originally installed.

4. RESPONSIBILITIES

4.1 Validation Team

· Prepare and approve the validation protocol.

· Provide training to the personnel regarding protocol execution.

· Assure complete adherence to the protocol during the execution

· Generate amendment to the validation protocol, as required.

· Document any deviations that occur during protocol execution.

· Document Operator SOP Training.

· Provide the resources required in executing the validation protocol.

4.2 PRODUCTION MANAGER

· Review the validation protocol and the final reports

4.3 QUALITY CONTROL/ASSURANCE MANAGER

· Approve the validation protocol and the final reports

5.0 Objectives:

To verify and establish that the Autoclave is working as per recommendations of the manufacturer.

6.0 Scope:

This validation protocol is applicable to the Autoclave intended to be used for steam sterilization in LARGE VOLUME PARENTRALS SECTION.

The protocol will be implemented under the following conditions

§ The validation of sterilization process using saturated steam as the steriliant

§ Prior to the production of a new sterilizer.

§ A change In the load design or weight that would result in a load that is more difficult to sterilize.

7.0 Equipment Identification

Equipment Name	Autoclave	Verified
Model Number		Yes ¨ No ¨
Serial Number		Yes ¨ No ¨
Make		Yes ¨ No ¨
Asset No.		Yes ¨ No ¨
Location		Yes ¨ No ¨

It has the following sub-components

S. No.	Description	Check
1	Time controller	¨
2	Pressure controller	¨
2	Temperature controller	¨
3	Pressure gauge	¨
4	Safety Valve	¨
5	Thermometer	¨

Completed By:__________________ Date:_____________

Reviewed By:___________________ Date:_____________

8.0 EQUIPMENT DESCRIPTION

The Autoclave intended to be used for steam sterilizations process. It has following specifications:-

S. No.	Parameter	Range	Readability	Check
01	Timer	0—60 min	1 min	¨
02	Pressure	0—60 Lb/inch²	2.0 Lb/inch²	¨
03	Temperature	0 –150°C	0.5°C	¨

8.1 LOAD IDENTIFICATION

Nature of load	1000ml bottles
Quantity of load	2000 Bottles

8.2 STERILIZATATION CYCLE PARAMETERS

Sterilization set point	106°C
Temperature range	106°C +0.5°C
Expose time	45 minutes

8.3 Equipment Used for PROCESS VALIDATION

Equipment	Calibration		Certificate No.	Issue Date
Equipment	YES	NO	Certificate No.	Issue Date
Recording potentiometer	¨	¨	___________	________
Thermocouples & lead wires	¨	¨	___________	________
Biological indicator i.e. B. stereothermophyllus	¨	¨	___________	________

Completed By:__________________ Date:_____________

Reviewed By:___________________ Date:_____________

9.0 strerilizatation procedure:

§ Place six thermocouples in the load at the slow to heat points as determined

Previously by(Heat Distribution and Heat Penetration studies)

§ Place thermocouples exterior and near to (Penetration TC)and expose to chamber steam distribution TC)

§ Place BIs (Biological Indicators) at each of the slow to heat penetration location.

§ Load autoclave extend TC out of autoclave and attach to potentiometer

§ Position one TC by controller record sensor

§ Close autoclave door

§ Perform, function check of TC .replace if defective.

§ Replace autoclave sensor chart with a new one

§ Check to make sure that cycle parameters are set

§ Set potentiometer for a 3.0 Hours scan cycle.

§ Initiate sterilization cycle and potentiometer cycle at same time

§ Allow cycle to continue until it is completed. Collect all potentiometers, controls and computer control record and place with protocol.

§ Have computer graph results and calculate Fo value. After load has cooled, remove BIs and have tested

§ Incubate BIs in incubator at 55Cº for 48 hrs

10.0 ACCEPTANCE CRITERIA

1- BDS Strip

All four colors segment of the processed indicator are black. If all other critical process parameters such as temperature, pressure and sterilization are in accordance with cycle reference.

2- Bio-Indicator i.e. B. stereothermophyllus

No growth should be observed after incubation for 48 Hours.

10.1 Results

Temperature : 106°C

Pressure : 10 Lb/inch²

Sterilization Time : 30 minutes

1- Evaluation of the BDS strip.

S.#.	Position of Indicator strip	Stick BDS-test indicator strip on	Acceptance Criteria		Results
			All four color segment of indicators strip are black
			Yes	No
1			¨	¨
2			¨	¨

2- Evaluation of the Bio-indicator i.e. B. stereothermophyllus

S.#.	Position of B. stereothermophyllus			Acceptance Criteria		Observation
				No growth is observed after incubation for 48 Hours
				Yes	No
1	Front/top left	Fornt/bttm center	Middle /centleft	¨	¨
2	Middle/ bttmleft	Rare/top center	Rare/bttm left	¨	¨
3	Front/top center	Front/bottm center	Middle/cent left	¨	¨
4	Middle/bttm right	Rare/top bottom	Rare/bottm center	¨	¨
5	Front/top right	Front/ bottmleft	Middle/ center	¨	¨
6	Middle/ Bttm/Cent	Rare/top right	Rare/bttm center	¨	¨

All acceptance criteria have been met. Verified By / Date

Yes ____________No _____________ _____________

If No or N/A, explain in Comments.

Comments:_____________________________________________________________

Completed By:__________________ Date:_____________

Reviewed By:________________ Date:_____________

11.0. Incidents/Deviations

To document any discrepancy or variations noted during the execution of the Process Validation Protocol. Any action to be taken to resolve an outstanding issue is to be identified within the incident report.

INCIDENT #	DESCRIPTION OF INCIDENT	RECORDED BY	DATE

COMMENTS:

____________________________________________________________

12.0 Final Comments about PROCESS VALIDATION

________________________________________________________________

13.0 SIGNATURE IDENTIFICATION SHEET

This sheet is a record of each individual who signs or initials any page included in this protocol or in the attached document. Each person shall be identified by typed or printed name.

Name Signature and Initials Company

__________________ _________________________ _____________________

__________________ ________________________ _____________________

__________________ _________________________ _____________________

FINAL APPROVAL OF QUALIFICATION

This document certifies that the process of Autoclavation has been validated as specified and complies with Standard Operating Procedures, and satisfies the requirements for cGMPs.

	Name & Designation	Signature	Date

Prepared By	Tahir Ibrahim Quality Assurance Executive

checked and Reviewed By	Abdul Hafeez Production manager

Approved By	Tajjamal A Qurashi Manager Quality Control

PROTOCOL TRAINING

Training Session Date : ____________________

Instructor : ____________________

Protocol Reference : ____________________

Name	Title	Signature	Date

SAP Validation Environment for Pharma Companies

2011-01-19T07:12:00.001-08:00

The pharmaceutical industry is responsible for all the development, production and supply of pharmaceutical product. These products are needed to save lives, prevent disease and helps in maintaining quality of life. Preparations must be safe and effective for patients & the general public. Preparation should be such that there is no risk to life or side effect involved. It must protect consumer. For this we need regulatory bodies who can control the preparation process of these products.
There are International reputed agencies who acts as Regulated bodies for Pharmaceuticals industry
Food & Drug Administration (FDA) –Relevant for US Market mainly
European Medicines Evaluation Agency (EMEA) –For European Region
Drug Controller General of India –For India
Following are the Regulation involved:
GxP: The term GxP means GMP (Good Manufacturing Practices) ,where ‘x’ includes
GCP (Good Clinical Practices)
GLP (Good Laboratory Practices)
GDP (Good Distribution Practices)
What is Validation?
Validation is a process of establishing documents that provides guarantee that if we follow a particular process consistently to produce a product we will be able to meet predetermined specifications and attributes.
Validations in Pharmaceutical Company
Process Validation: This involves validation of Manufacturing Process, Plant & Machines, and Manufacturing Techniques etc.
Cleaning Validation: This involves validation of Labs, Production, Packaging (Proof of clean), Equipments, Machinery, Instruments, Cleaning Techniques etc.
Method Validation: This involves validation of Laboratory methods (R&D…), Quality Verification methods, Analytical Equipment etc.
Computer System Validation: This involves validation of Computer Related Systems (any place), Computer Systems & Operating procedures, Design, Installation, Performance etc.
V Model Concept for System Validation
Below is universally accepted model popularly known as V model for validation

V Model Concept for System Validation
User Requirement Specifications (URS) : This step defines what user wants from the system and makes sure that requirement is met
Functional Specifications: This step defines or creates a document in user understandable format based on URS. This is developed by developer or vendor or service provider.
Design Qualification DQ: This step provides a document which states that the computer system requirements have been clearly defined and is approved in the form of URS. It also provides document that states all additional system specifications are developed, reviewed and approved.
Installation Qualification IQ: In this step document is provided which gives the guarantee that all hardware installation aspects are considered according to appropriate codes and approved design. Also software installation is also considered.
Operation Qualification OQ: In this step document is provided which gives the guarantee that installed system works as specified.
Performance Qualification PQ: In this step document is provided which gives the guarantee that entire system performs as expected under all operating ranges.

Nikita Chitre

ArchitectSAP Solutions
SAP. Streamlined.

SAP System Validation and Compliance Methodologies for Pharma Companies

2011-01-19T07:09:00.000-08:00

The SAP system setup for Pharmaceutical companies is same as any other industries/organizations; just Pharma companies are regulated by special Government bodies by the state. This is because Pharma companies manufacture medicines and other products which are essential for maintaining good human life and hence are sensitive entities. To launch any new pharmaceutical product in the market, it has to be rigorously tested and test results documented and are verified by the regulating bodies. To carry out SAP system validation of a pharmaceutical industry which has implemented SAP, one should gather basic knowledge of all interfaces of SAP and the FDA guidelines for the product about the interface to internal and external hardware and software taking into account.
There are different regulatory bodies for pharma companies in different countries like:
Drug Controller General of India – For India
FDA – Food and Drug Administration for US
EMEA – European Medicines Evaluation Agency
Following are the reasons that explain the need of regulation for Pharmaceutical industry:
Quality assurance – Pharmaceutical companies produce drugs, medicines and medical equipments which are used by hospitals worldwide for treating patients. Thus the manufacturing process of these must be very hygienic, safe and of top quality.
Government Policies – The Government has some guidelines, rules and procedures for pharmaceutical companies and it has its dedicated team of representatives who conduct regular inspection checks along with surprise visits to the pharmaceutical companies. This is to ensure that best practices are being followed while producing life saving materials.
Upgradation – With the changing world and market scenarios, the rules and procedures need to be analyzed, studied and modified, if required. Also new steps or rules may be added.
Following are the general basic steps involved in all the Validation processes:
Gap Analysis – GAP here means incompleteness or missing links. GAP analysis means analyzing the SAP system through available documentation, and current status of SAP with reference to the guidelines of Regulatory agencies and attempt to find out from available implemented systems.
Plan of Action – Based on our gap analysis we create action plan along with client, and decide which gaps can be closed technically and which are to be attended by other procedures. There may be some offset in closing the Gaps.
Risk Assessment – After the plan of action, we will carry out detailed Risk Assessment of relevant modules. If required the Human resource module and distribution part is also analyzed. In this step, we determine the important transaction codes and classify them into typical three categories as per GAMP guidelines. The further validation procedure is based on this classification.
Validation - This step is the formal start of validation process with the creation of VMP or Validation Master Plan. Then comes the protocols preparation.
Computer System Validation (CSV)
This method is to verify whether the computer systems are delivering their part. It includes hardware, software and the firmware. This method requires detailed documentation of the software or application used by the manufacturing process in the Pharma company.
The documentation involves:
List of hardware required
Minimum hardware required to maintain the SAP support system
Functional specification about the requirement
Applications and benefits
Test results with comments/feedback.
Following are some of the problems that may arise during a validation project:
Difficulty in understanding the requirement if the documentation i.e. the functional specification is not proper.
Secondly, in most of the cases, the validation group is assigned task only after the SAP has been implemented in the industry and is in function for more than year. So here it is difficult to recognize what output the system was supposed to produce. To overcome this problem we should seek guidance and expertise of experienced functional consultants of all modules.
We also need to define the present requirements. For this we have build a central team which consists of all kinds of users as well as senior representatives from Quality Assurance, Quality Control, IT Dept and Validation and partial finance persons.

Abhijeet Kapgate

ArchitectSAP Solutions
SAP. Streamlined.

Validation of Equipment – Pharma Industry

2011-01-19T07:07:00.000-08:00

The concept of validation was first developed for equipment and processes. In 1993 the software for a large radiotherapy device was not designed and tested properly. Several problems resulted in several devices giving doses of radiation higher than intended. Because of that several patients died and several got permanently injured. That is why validation of equipment is required for pharma industry. Following are the steps followed to do validation of equipment in SAP and how to create link between maintenance order and calibration order.
Validation of Equipment after Corrective Maintenance by QC in SAP.
When Equipment Breakdown is reported by Production, Maintenance Person gets a break down order. He attends the Breakdown through Breakdown order.
After solving the issue Maintenance person submit the Equipment to Production for check/dry run
Then Production person will raise a Request for Validation to Quality department.
Quality person will validate the Equipment through calibration order. They will check all the parameters, Room Temperature, humidity & also the parts replaced by maintenance etc. according to details mentioned in the Maintenance order.
After completion quality person will revert back to Production, Production gives approval to close the Maintenance order.
To create link in SAP between Maintenance order and Calibration order, you can use suborder concept.
In SAP create a maintenance order PM01 for break down, and then create a calibration order PM05 as sub order (IW36). You can settle the sub order to a different cost center, so that calibration order cost is settled to Quality department.

Nikita Chitre

ArchitectSAP Solutions
SAP. Streamlined.

FDA’s Process Validation Guidance Calls for Technology Solutions

2011-01-02T03:48:00.001-08:00

As the FDA gathers feedback and finalizes its “Guidance for Industry—Process Validation: General Principles and Practices” draft published in November, life sciences companies are looking carefully at the updated recommendations and how to apply changes to their own process development and manufacturing capabilities.
These updates to the 22-year-old guidelines are welcomed by those of us who are passionate about manufacturing process excellence. Leaps and bounds have been made in fundamental enabling technologies since the FDA first published its original guidance on process validation in 1987. For perspective, ’87 was the year Sun Microsystems introduced the SPARC processor and IBM launched its PS/2 personal computer with a 3.5-inch diskette drive. We were still recording on paper-based systems and many years away from cost-effective storage of large amounts of electronic data—let alone the ability to access and leverage such data as the basis for decision making.
Today, as life sciences manufacturers continue to catch up to technologies’ new capabilities, many have migrated to electronic systems and records, but they are still not able to provide self-service access and aggregation of data for end users in a context that allows them to easily understand their processes and capitalize on potential improvements.

“You absolutely have to have appropriate software capabilities in place.”

They have to request and search manually through mountains of data from disparate sources—enduring the “spreadsheet madness” that makes problem-solving time consuming and error-prone. The FDA draft’s emphasis on using data continuously for validation makes the accessibility and analysis of process data more important than ever from a regulatory perspective. The updated guidelines define process validation as “the collection and evaluation of data, from the process design stage throughout production, which establishes scientific evidence that a process is capable of consistently delivering quality products.” Now, on-demand access to the right data in the right context for analysis becomes central to Performance Qualification.
To leverage knowledge and understanding as the basis for establishing an approach to control that is appropriate for the manufacturing process, the FDA guidance recommends that manufacturers:
• Understand the sources of variation
• Detect the presence and degree of variation
• Understand the impact of variation on the process and ultimately on product attributes
• Control the variation in a manner commensurate with the risk it represents to the process and product.
The document says, “Process validation involves a series of activities taking place over the lifecycle of the product and process.” The FDA describes in detail process validation activities in the following stages, saying, “In all stages of the product lifecycle, good project management and good archiving that capture scientific knowledge will make the process validation program more effective and efficient. These practices should ensure uniform collection and assessment of information about the process, reduce the chance for redundant information gathering and analysis, and enhance the accessibility of such information later in the product lifecycle.”
To fully apply the FDA’s current thinking in process development and manufacturing, you need the right technology tools. While PAT implementations have been encouraged by the FDA for years—especially in the agency’s risk-based approach initiative—this is probably the most important published guidance that ties technology to process validation practices in a way that spans process development, quality and manufacturing. You absolutely have to have appropriate software capabilities in place to access, aggregate, analyze, understand the information content and report data on-demand by end users in a meaningful context, such as one that allows correlation of upstream parameters with downstream process outcomes (automatically accounting tor batch genealogy), during both process design and commercial operations.
The FDA is pointing manufacturers to practices that can continuously improve their process understanding and, therefore, make the process validation program more effective and meaningful. Like many of its regulatory efforts and mandates, what is good for the FDA and consumers is also beneficial for manufacturers. In this case, leveraging data in the right way can enable greater Process Intelligence, which helps control variability and improve quality, results in higher yields and speeds time to the commercial market.
The new document states, “In addition to being a fundamental tenet of following the scientific method, information transparency and accessibility are essential so that organizational units responsible and accountable for the process can make informed, science-based decisions that ultimately support the release of a product to commerce.”
This is certainly a progressive step forward for the FDA and a win-win situation for an industry ready to embrace technology tools for improvement.

About the Author
Justin O. Neway, Ph.D., is executive vice president and chief science officer at Aegis Analytical Corporation. He has more than 25 years of experience in pharmaceutical and biotechnology manufacturing, and in the development and application of software solutions to quality compliance and operational efficiency in life science manufacturing.

Computer System Validation: Are You Ready for an Inspection?

2011-01-02T03:47:00.000-08:00

Is your organization ready for an inspection of your Computer System Validation program? In this article, I will offer some key tips on how to prepare for an inspection of your computer system validation (CSV) program. Often times, the FDA comes to inspect your facility for reasons other than your CSV program. However, because so many of our business processes are governed by electronic systems, the topic of Computer System Validation inevitably comes up during the course of an inspection. As a result of an increase in federal investigators, investigators are able to inspect more facilities and dig deeper into areas such as Computer System Validation.
The very first item you can prepare is a system inventory list. The list itself should be organized by GxP (GCP, GLP or GMP) so you can sort the list accordingly during an inspection or for analysis purposes. Next, the list should include a system owner for each system so you know who is responsible for the system and who to call upon during an inspection.
Another important piece to include is the location of the computer system validation documentation, as this is not only important from a storage aspect, but also an access point of view. Under everyday operations, one should have easy access to this documentation. During an inspection, it is key to have quick access to such documentation, as investigators do not like to wait too long for documents they request. The last attribute to include in your system inventory list is an indicator of whether or not a system is critical. To determine criticality, it is wise to determine whether or not a system is used for regulated purposes or used to make decisions as they pertain to regulatory requirements. Flagging these can not only help you better prepare for an inspection, but also better allocate your resources more effectively for the inspection preparation activities.
The second item you should ensure you have in place is governing Standard Operating Procedures (SOPs). You should have the following SOPs in place for compliance and operational purposes as well as inspection purposes. The first important SOP to have in place is the Computer System Validation SOP. This SOP should outline and detail the Validation Lifecycle. It should include requirements for key areas such as Intended Use, Validation Master Plan, User and Functional Requirements Specification, System Design Specification, Traceability Matrix, Installation Qualification, Operational Qualification, Performance Qualification, Validation Summary Report, and System Release Memo. Investigators will want to see that you detailed the requirements for all of your deliverables in the Validation Lifecycle. Furthermore, they will look to ensure the deliverables have the right dependencies and are in the correct order.
The second SOP to have in place is the Software Development Lifecycle (SDLC) SOP. This SOP should outline the steps needed to perform the SDLC for custom applications and should handshake with the Computer System Validation SOP.
The third SOP to have in place is a Change Control SOP. The Change Control SOP should describe the process for controlling both software and hardware in the production environment. Furthermore, the SOP should require a Change Control Board that is responsible for reviewing and approving all changes. It is also important to include a classification of change. For example, there should be three classifications: Minor, Major, and Emergency. Classifying the changes helps manage the change control process more effectively.
Assembling a Change Control Board and classifying changes gives inspectors a good sense that your process is in control, as it shows you are well organized when assessing changes. It is notable to mention there are an increasing amount of 483s and Warning Letters for companies failing to exercise change control and perform computer system validation for their respective systems.
The fourth SOP to have in place is a Bug and Issue Tracking SOP. This SOP is becoming increasingly important, as regulators are asking more questions when it comes to how bugs and issues are handled. Therefore, it is important to have a mechanism in the Bug and Issue Tracking SOP to handle whether or not validation is required as a result of fixing a bug or an issue. Investigators often look for this mechanism.
A fifth SOP that is an important aspect of inspections is a Good Documentation Practices SOP. It is very important o have a structure in which to document your evidence of validation activities. Deploying good documentation practices helps ensure the integrity of your computer system validation and change control documentation. Investigator are quick to point out documentation errors when reviewing documentation, therefore, it would be prudent to have a sound Good Documentation Practices SOP in place. Please remember there is a good amount of documentation when it comes to computer system validation.
An important aspect of preparing for inspections is to prepare critical documentation for review by an investigator. How do you determine what is critical? Well, a good first step to determining what is critical is to determine what system are used for regulatory purposes or to make decisions as they pertain to regulatory requirements. For example, an obvious application is your Adverse Event Reporting System, which handles Adverse Events that are reported to the FDA. A Documentation Management System is another example of a critical system, as it is often used to manage and store regulated documents. What validation documents for your critical systems should you be reviewing? There are some documents that are prone to mistakes so I would recommend these types of documents be reviewed first.
An example of a document that is error prone is your test scripts. There are two important points to look for here. First, you want to ensure the test scripts are legible and free of errors. Secondly, you want to ensure the test scripts have the appropriate objective evidence attached to them. This is a very important point to bear in mind, as investigators often like to see objective evidence. What do I mean by objective evidence? Objective evidence is evidence that a test script has met its objectives. A great example of how to capture objective evidence is through screen shots. However, be careful where to require screenshots, as you only want screenshots that prove the test script met its objective. Otherwise, you end up with too many screenshots that do not necessarily prove the test script has met its objectives.
Another important document to review prior to an inspection is your Traceability Matrix. Your Traceability Matrix ensures your intended use of the system has been tested through test scripts that map to a set of approved requirements. Investigators are now reviewing Traceability Matrices to ensure the system is tested effectively against it s system requirements. I encourage the review of this document during the end of your validation efforts and prior to approving the Traceability Matrix. However, it is a good idea to double-check your Trace Matrix before an inspection, as an investigator can find one requirement that was not tested and therefore declare that your system has not been validated per its intended use and there is not validated. As you can see, the Trace Matrix is a very important document.
The last document to review before an inspection is your System Release Memo. The System Release Memo signifies the system has been released into production. Some important point s to check here are the dates. It would be advantageous to ensure your signature date of your System Release Memo is after the signature date of your Validation Summary Report. Small items like these are often overlooked by companies, as there is usually a rush to release systems into production and sometimes it happens before the documentation is complete. There is no explanation for errors like these, as it shows you are not following your SOPs and that will be the nature of the 483 observation if an error like this is found by an investigator.
In conclusion, there is much to consider about your Computer System Validation program prior to an inspection. Remember to have a system inventory list in place, the proper SOPs in place, and to inspect your critical systems and their documentation prior to an FDA inspection. Again, just because the FDA may be inspecting your facility for other reasons, doesn’t discount the possibility they will want to audit your Computer System Validation Program. As stated, so many of our respective business processes are carried out by way of electronic systems in this age of technology. Therefore, it would be advantageous to assess your Computer Validation Program whether you foresee an inspection or not. Having an efficient Computer System Validation Program in place helps ensure the integrity of your electronic records, allocate resources more effectively and therefore can yield long term cost savings to your company.

Staffing, Training and Validation Are Critical to PAT

2011-01-02T03:43:00.001-08:00

By Paul Thomas, Managing Editor

Many manufacturers are “doing” PAT these days, but few individuals truly have a grasp of what it means and what its potential is in the pharmaceutical industry — for process monitoring, and design and control as well.

One who knows PAT inside and out is Bruker Optics’ VP Dan Klevisha. Klevisha has been trying for years to convince pharma firms of the merits of PAT. Only since FDA put its full weight behind analytical technologies like those Bruker offers — such as process monitoring IR, NIR and Raman — was he able to make significant headway. Seventeen of the top 20 pharmaceutical firms are now using Bruker for some sort of PAT application, he says.

I sat down with Klevisha at last month’s Pittcon show in Orlando, and picked his brain about PAT and where it’s headed.

Bruker developed its Tandem on-line NIR device for monitoring tablet uniformity at a major pharma firm's request; there was no market for such an instrument before FDA began promoting PAT.

What is different about PAT these days? I asked. Unlike a few years ago, he said, every firm has committed substantial resources and has a defined organizational strategy to approach PAT. “The manufacturing segment of pharma has finally accepted PAT for real,” he said.

Some firms have been vocal about their PAT efforts, others not so. While he won’t name names, Klevisha says some of the firms leading the pack in terms of progressive PAT strategies are those we hear least from.

What’s the greatest risk firms face in implementing PAT? There are two, Klevisha said. First, “they have to make sure that they have a sufficient staffing commitment to support the deployment of a PAT system. This includes having people qualified to transfer that knowledge to the manufacturing staff.” There’s a very long learning curve for PAT applications, he added, and firms need to commit to thorough training programs for personnel.

Finding experts to train the manufacturing ranks is not easy, he said. “Process analysis experts from chemistry, defense, and telecom are in heavy demand,” Klevisha said. “The challenge is that these individuals don’t have experience in a pharmaceutical environment.”

The second greatest risk is validation of PAT-enabled processes. “The industry has a good sense of validation and equipment qualification,” he said. “But that has to be rethought for PAT. Traditional validation processes are too time-consuming and expensive.” Costs of PAT equipment, in fact, can be dwarfed by the cost of validating its use, Klevisha said. Understanding the science behind PAT will be key for firms to solve validation issues.

An understanding of processes grounded in science is, of course, what FDA is looking for. I asked Klevisha what FDA’s PAT initiative has meant to his and Bruker’s business. Bruker has focused on PAT instrumentation for more than 12 years, he noted. But for most of those years, few pharmaceutical firms expressed even the slightest interest in process analytical technologies and systems. As a result, Bruker had no need to pursue technologies that it had within its grasp.

That has changed dramatically since the initiative. Klevisha used the example of the company’s Tandem on-line NIR device for monitoring tablet uniformity. After FDA’s change of course, a major pharmaceutical firm asked Bruker to develop the device. “Without PAT, we would not have developed it,” he said. “There would have been no market.”

Where is PAT headed in the next two or three years? "In that time, we’ll have a firmer understanding of successful applications," Klevisha said. Right now, comprehensive PAT strategies are just getting under way and offer no real lessons to speak of. With trial and error will come experience. For Bruker, Klevisha believes, that will translate into better and less expensive tools and solutions, and easier and faster deployment.

When payback is realized, investment will increase, he continued. “Firms will demand robust, single-purpose, application-specific devices,” he predicts. One company in another industry has already implemented more than a hundred different Bruker devices, Klevisha noted. Eventually, pharmaceutical firms will have similar needs.

The “Intended” Consequences of Software Validation

2011-01-02T03:42:00.000-08:00

With the growing importance of information management and electronic documentation within the pharma GMP world, it was only a matter of time until regulators made software validation a focal point of their work. “The FDA has increased its awareness of software validation and investigators are now more mindful of it during the inspection process,” notes Michael Gregor, CEO of Compliance Gurus (Boston, Mass.). “In fact, FDA investigators are after objective evidence of regulated applications requiring software validation.”
Most manufacturers have yet to adapt to this change, says Gregor, but they now have little choice. In this conversation, Gregor offers insight into the fundamentals, and pitfalls, of software validation efforts:
PhM: What’s behind FDA’s increased awareness of software validation, and has it caught manufacturers off-guard?
M.G.: An increase in federal investigators has allowed the FDA to concentrate on a more broad range of regulations. Yes, many manufacturers have been caught off-guard.
PhM: What’s the status of software validation guidance, and are there updates on the horizon?
M.G.: There are no updates to software validation on the horizon. There was a pledge by the FDA to update 21 CFR Part 11, Electronic Records and Electronic Signatures, but they have yet to provide any further guidance or update the final rule itself.
PhM: What are some of the pitfalls you see with software validation projects?
M.G.: The biggest pitfall is the lack of good requirements. Requirements are the source of the system functionality and design and therefore should be properly written. Another pitfall is the lack of traceability from requirements to test scripts. Lastly, there is a lack of adherence to change control procedures, therefore resulting in systems no longer maintaining a validated state.
PhM: Why is this happening? Aren’t validation teams prepared or competent enough?
M.G.: Many teams are facing tight deadlines, which contributes to the lack of attention to planning and detail. Oftentimes validation teams are rushed through the process and therefore many key validation attributes are overlooked. There is a lack of a representative group to author requirements. Too many times requirements are written in a vacuum!
A good practice for establishing solid system requirements is to ensure you have a representative group involved in the author, review, and approval of system requirements. Typical and recommended representatives are: Quality Assurance, Users, and IT.
PhM: How about change control? What’s the secret to continued validation?
M.G.: The trick to maintaining your validated systems in a validated state is to have a change control procedure that covers both software and hardware changes. The procedure should also require a representative group to reside on a change control board. Again, recommended members are: Quality Assurance, IT, and the User community. It’s important to note that more than one user is okay and even encouraged, as it is not only important to assess the impact of the change to the system, it is also important to understand the impact of the change to the business.
PhM: Are COTS [commercial off-the-shelf] vendors providing better validation packages than in the past, and should manufacturers still be wary of software products that come with “complete” validation packages?
M.G.: Great question. The quality of validation packages has been consistently poor and they continue to lack the quality needed to pass FDA standards. COTS vendors fail to realize that objective evidence is needed to prove a system operates as intended. Furthermore, oftentimes COTS applications are highly configured and therefore require a level of validation that is much more significant than the standard “out of the box” test scripts provided by COTS vendors.
PhM: As more manufacturers are taking advantage of Software-as-a-Service and “hosted” options, are there special validation considerations they need to be aware of?
M.G.: Yes, there are several considerations where security is concerned. Both physical and network security are crucial when an application is hosted by a third party. Validation considerations are security, change control, and installation.
PhM: What is “intended use” and why do manufacturers struggle to interpret its true essence?
M.G.: As the name implies, it describes how a software application is intended to be used. Intended use drives the need for validation and also leads the way for system requirements, which are a key component to any validation effort. Manufacturers struggle with the concept because they often lack the procedural controls to identify and define “intended use” in the first place.
PhM: How prevalent are warning letters related to “failure to validate computer software for its intended use,” and what are the underlying issues that the Agency is calling out?
M.G.: Warning letters related to the failure to validate software are not too common. However, in the last year, this has changed, as the FDA as stepped up efforts and has become more vigilant when it comes to software validation and intended use.
PhM: A lot of new products are coming on the market for analytical and modeling applications (to assist in Quality by Design efforts and other work). Might there be specific intended use issues (or general validation issues) for these types of products?
M.G.: Applications of these types are often complex applications. The more complex the application, the more difficult it is to properly validate for its intended use. In most cases, proper requirements are often lacking with complex applications. This alone can cause a validation effort to fail, as system requirements are the root to system functionality and design.

QbD for Better Method Validation and Transfer

2011-01-02T03:39:00.000-08:00

More companies in the pharmaceutical industry today are adopting the principles of Quality by Design (QbD) for pharmaceutical development and manufacturing. Described in ICH Q8, Q9 and Q10 guidance documents, QbD enables enhanced process understanding, and a more systematic and scientific approach to development, so that better controls may be implemented. The end goal is more robust manufacturing processes than those that typically result from traditional approaches to drug development.
The QbD framework has many implications for manufacturers and regulators alike. This article describes how analytical methods can be viewed as "processes" and QbD concepts applied, to improve both method validation and transfer. Its goal is to stimulate thinking and discussion on how analytical method validation and transfer could evolve as industry increasingly adopts Quality by Design concepts.
But QbD cannot be considered without examining validation within a product lifecycle framework. The U.S. Food and Drug Administration (FDA) attempted to do just that in a recent draft guidance [1] designed to help achieve the goals of its “Pharmaceutical GMP's for the 21st Century – A Risk Based Approach” [2].
This guidance addresses some of the problems with traditional approaches to process validation, which were articulated by Moheb Nasr nearly five years ago [3]. Too narrow a focus on a "three-batch" approach to validation has encouraged a "don't rock the boat" mindset within the industry that can fail to foster continuous improvements in quality or efficiency.

The Need for Real World Verification

The same problems can be seen in analytical method validation and transfer, where the focus often shifts from ensuring the robustness of the method itself to ensuring the robustness of the documentation, and how well it will withstand regulatory scrutiny.
Methods for pharmaceutical products are normally validated by experts who have developed the method in accordance with ICHQ2 guidance (Validation of Analytical Procedures: Text and Methodology) or USP <1225> (Validation of Compendial Procedures). However, validation can be treated as a one-off event, with little consideration given to verifying how well the method will perform at everyday, "real world" operating conditions. All too often, regulators and industry use ICH Q2 or USP <1225> in a “check box” manner without considering the intent of these guidances, or the philosophy of method validation.

These issues continue after the method has been validated, when it is transferred to another laboratory. This transfer step requires that the knowledge of how to operate the method be transferred to those who will use it routinely, and that an exercise be performed, documenting that similar results have been obtained by both parties.
The transfer exercise is usually performed by the most competent analytical staff in the receiving laboratory, yet it may have little relationship with how the method will be used in routine, day to day operations.
It may come as little surprise, then, that most methods fail to perform as intended in the receiving laboratory, triggering efforts to identify variables that are causing the discrepancies, and repeated, costly testing and documentation.
The roots of method transfer failures can usually be traced to insufficient consideration of the routine operating environment during the method validation exercise, and lack of an effective process for capturing and transferring the tacit knowledge of the development analysts.

A QbD Framework for Analytical Method Life Cycle Management

If an analytical method is viewed, simply, as a process, whose output is data of acceptable quality, QbD concepts designed for manufacturing processes can be applied to analytical methods [4]. Thus, the concepts of lifecycle validation that are being developed for manufacturing processes might also be applied to analytical methods.
QbD is defined as “a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding based on sound science and quality risk management” [5] and FDA [2] has proposed a definition for process validation that is “the collection and evaluation of data, from the process design stage throughout production, which establishes scientific evidence that a process is capable of consistently delivering quality products.”
When considering a lifecycle approach to method validation, a similar definition could be adopted “The collection and evaluation of data and knowledge from the method design stage throughout its lifecycle of use which establishes scientific evidence that a method is capable of consistently delivering quality data.”

From these definitions, it can be seen that there a number of key factors that are important in a QbD\Lifecycle approach. These include:

The importance of having predefined objectives
The need to understand the method, or being able to explain the method performance as a function of the method input variables
The need to ensure that controls on method inputs are designed such that the method will deliver quality data consistently in all the intended environments in which it is used
The need to evaluate method performance from the method design stage throughout its lifecycle of use.

In alignment with the approach proposed in the draft FDA guidance for process validation, a three-stage approach could be taken with method validation. (See chart.)
Stage 1 – Method Design: Define method requirements and conditions and identify critical controls
Stage 2 – Method Qualification: Confirm that the method is capable of meeting its design intent.
Stage 3 – Continued Method Verification: Gain ongoing assurance to ensure that the method remains in a state of control during routine use.

Stage 1 - Method Design

The Method Design stage includes establishing the method performance requirements, developing a method that will meet these requirements and then performing appropriate studies to understand the critical method variables that must be controlled to assure the method is robust and rugged, The method design stage can be an iterative process which is repeated as required in accordance with the lifecycle phase of the product.
Method Performance Requirements
Utilising a QbD approach, it is essential at this stage that sufficient thought be given to the intended use of the method and that the objectives or performance requirements of the method be fully documented. This represents the Analytical Target Profile (ATP) [6] for the method.
To draw a parallel to qualification of new analytical equipment, the ATP for the method is effectively the equivalent of a User Requirement Specification that would be produced to support qualification of new analytical equipment (or the Design Qualification as defined in USP <1058>).

To build the ATP, it is necessary to determine the characteristics that will be indicators of method performance. Typically these characteristics will be a subset of those described in ICH Q2, such as accuracy or precision.
It is important, however, not to use the ICH Q2 characteristics in a check box manner but to consider the method's intended use. For example, the characteristics that are critical to the performance of an HPLC assay method intended to be used to quantify the active ingredient within a tablet might be quite different from those of an NIR method intended to be used to measure the end point of a blending operation. In the second case, accuracy may not be a critical method performance requirement in determining homogeneity.
Once the important method characteristics are identified, the next step is to define the target criteria- in other words, how accurate or precise the method should be. A key factor in choosing the appropriate criteria is the impact of method variation on the overall manufacturing process capability. Knowledge of the proposed specification limits and the expected process mean and variation is helpful in setting meaningful criteria.
Method Development
Once the ATP has been defined, an appropriate technique and method conditions must be selected in order to meet the requirements of the ATP. While method development is a very important part of the method lifecycle, it is not necessary to elaborate here since it has been extensively addressed in the literature.
Method Understanding
Based on an assessment of risk (i.e. the method complexity and the potential for robustness and ruggedness issues) one can perform an exercise focused on understanding the method to better understand what key input variables might have an impact on the method's performance characteristics. From this, one can identify a set of operational method controls.
Experiments can then be run to understand the functional relationship between method input variables and each of the method performance characteristics. Knowledge accumulated during the development and initial use of the method provides input into a risk assessment (using tools such as the Fishbone diagram and FMEA) which may be used to determine which variables need studying and which require controls.
Robustness experiments are typically performed on parametric variables using Design of Experiments (DoE) to ensure that maximum understanding is gained while minimizing the total number of experiments. Depending on the type of method, surrogate measures of characteristics such as accuracy or precision may be evaluated. An example might be peak resolution in a chromatographic method. It follows that well designed System Suitability requirements can be a valuable tool for assuring that a method is operating in a region where the ATP requirements will be met.
When developing an understanding of the method’s ruggedness, it is important to consider variables that the method is likely to encounter in routine use, such as in situations involving different analysts and different instruments. Tools such as measurement system analysis can be useful in providing a structured experimental approach to examining such variables.
Method Design Output A set of method conditions will have been developed and defined which are expected to meet the ATP. Those conditions will have been optimized based on an understanding of their impact on method performance.

Stage 2 - Method Qualification

Once a set of operational method controls has been determined during the design phase, the next step is to qualify that the method will operate as intended. In a similar manner to equipment qualification, method qualification can be broken down into the stages of method installation qualification (MIQ), method operational qualification (MOQ), and method performance qualification (MPQ).

Method Installation
Qualification focuses on ensuring that the facility where the method will be used is prepared to use it. This process includes ensuring that the analytical equipment is qualified and that appropriate knowledge transfer and training of analysts has been performed.
The method conditions and detailed operating controls, along with all the knowledge and understanding generated during the design phase, must be conveyed to staff at the facility in which the method will be used. Performing a “method walkthrough” exercise with both the development and routine analytical teams can be extremely valuable in ensuring all tacit knowledge about the method is communicated and understood.
The extent of the IQ phase may vary depending on the level of pre-existing knowledge of the routine testing laboratory with the product, method or technique. For example, the laboratory that originally developed the method may merely ensure that other personnel who will use the method are trained.
The Method Operational Qualification phase is focused on demonstrating that the method meets its design intent. It is similar to “traditional method validation.” In the lifecycle approach, however, the focus is not about performing the traditional check box exercise to demonstrate compliance with ICH Q2. Instead, it is about demonstrating that the method meets the specific requirements that have been pre-defined in the Analytical Target Profile. A fundamental principle of this stage is that it should build on information that may have been generated in experiments already performed; for example, evidence of the selectivity or limit of quantification of a method may already exist from studies performed as part of method design.
The final stage in the qualification phase is to perform a MPQ exercise. At this stage, the actual manufactured supply samples are tested in facility, equipment and by personnel that will be used for routine analysis. The method should be operated exactly in accordance with the defined method controls and local operating procedures. As with the IQ stage above, the extent of the PQ exercise could vary, and would include for example confirming system suitability criteria are being routinely met.

Stage 3 - Continued Method Verification

The goal of this stage of the method lifecycle is to continually assure that the method remains in a state of control. This should include an ongoing program to collect and analyze data that relate to method performance---for instance, by setting criteria for replication of samples or standards during the analysis, by trending system suitability data or by trending the data from the regular analysis of a reference lot.
This activity aligns with the guidance in USP chapter 1010 on system performance verification. Close attention should also be given to any out of specification (OOS) or out of trend (OOT) results generated by the method once it is being operated in its routine environment. Ideally, using the new approach, laboratories should encounter fewer OOS results. If they do, it will be easier for staff to determine their root cause.
Change Control During the lifecycle of a product, both the manufacturing process and the method are likely to experience a number of changes brought through unintentional deviations, continuous improvement activities or the need to operate the method and\or process in a different environment. It is essential that all changes to the method operating conditions be considered in light of the knowledge and understanding that exists on the method performance. If the method operating conditions are modified such they fall outside the known method operable region (determined as part of ‘method understanding’ during the original design phase) then the Method Qualification should be revisited. Likewise if the process changes and samples contain analytes at levels outside those covered in the method operational qualification exercise or have new interferences, a new ATP would need to be generated and a partial re-qualification exercise will be required to ensure the method is still capable of producing consistent and reliable results for the extended range or modified sample.
Where a method needs to be transferred to new location, appropriate Method Installation Qualification activities (including knowledge transfer) will need to be performed in addition to a Method Qualification exercise.
Consistent with QbD principles, the extent of requalification should be driven by scientific principles, as described previously

Other Scenarios

The approach to method qualification described above focuses on the activities that would typically be performed when a method is developed and used within a single company. Other scenarios exist where a laboratory may need to use a method for which it has no access to the original method design or qualification information such as in a contract testing laboratory. In these situations, it is important that an ATP is defined and documented. An appropriate qualification study is then performed to demonstrate that the method meets its ATP. This approach could also be applied to qualification of a pharmacopoeia method. By applying the lifecycle approach to pharmacopoeia methods it is envisaged that there would be no need for a separate USP chapter on method verification (USP <1226> Verification of Compendial Procedures).
Another scenario that needs to be considered is when a method is used to support drug development rather than drug manufacturing activities. In this case the method will still need to produce data that is scientifically sound - particularly as it may be used to release material for clinical supplies, support stability studies or support the development of process understanding. At this point in the product lifecycle however the focus is on understanding the method performance rather than demonstrating that it meets predefined acceptance criteria.

A key advantage of this approach for the above scenarios is the flexibility to perform a qualification against the specific ATP defined for the intended use of the method. This eliminates the current desire to create a qualification document against ICHQ2 in a check box manner which can lead to unnecessary headaches and additional work.
Since there is the potential for this approach to be adopted for all users of analytical methods, it also offers the potential to standardise the multiple, misrepresented terminology which currently exists within the industry. It would result in a harmonised method qualification approach with standardised terminology which would remove the current state of confusion between the terms; method validation transfer and verification and the many interpretations as to what is actually required for each.
In short, adopting a QbD approach to analytical method lifecycle management would have some significant implications for analytical scientists in the pharmaceutical industry. First, ICH Q2 and pertinent USP chapters would need to be revised to align with the lifecycle validation concepts described above. (The need for a revision of ICH Q2 as a consequence of increasing adoption of QbD concepts and use of PAT has also been identified [7].
The activities that were previously defined as “method transfer” (that is, knowledge transfer and confirmation of equivalence) would become a central component of the lifecycle validation approach (in other words, they would be described as method qualification activities) rather than being treated as distinct from validation.
Likewise, method validation as described in USP chapter <1225>, method verification as described in USP chapter 1226 and the proposed USP chapter on Transfer of Analytical Procedures would be encompassed within the lifecycle approach and it may be logical to combine those chapters.
The CMC section of regulatory submissions may also need to change. In a Quality by Design rather than “Quality by Testing” paradigm, it seems inappropriate that the validation details of the test methods should fill such a large proportion of a submission. With a lifecycle approach to method validation the submission would see an increased focus on the method design aspects and demonstration of the work performed to arrive at method understanding. This would parallel the increasing focus on process understanding in submission which has arisen since the introduction of ICH Q8.
Review of formal method qualification activity would become an inspection issue rather than a registration issue. Underpinning this approach is the need for effective lifecycle management of knowledge and understanding of the analytical method.
In summary, the switch to a QbD approach to method development is already beginning to bring improvements to the performance of analytical methods. It is now time to look to modernize and standardize industry’s approach to method validation and transfer. By aligning method validation concepts and terminology with those used for process and equipment qualification, there is an opportunity to both reduce confusion and complexity for analytical scientists as well as to ensure that efforts invested in method validation truly add value, rather than simply being a check box exercise.

Glossary:
Analytical Target Profile (ATP)
The combination of all method performance criteria that direct the method development process. An ATP would be developed for each of the attributes defined in the control strategy and defines what the method has to ‘measure’ (i.e. acceptance criteria) and to what level the measurement is required (i.e. performance level characteristics: e.g. precision, accuracy, working range, sensitivity and the associated performance criterion).
Method Development The collection of activities performed to select an appropriate technique and method conditions that should have the capability to meet the ATP requirements.
Method Understanding (MU) The knowledge gained from the collection of activities performed to understand the relationship between variation in method parameters and the method performance characteristics.
Method Installation Qualification (MIQ) The collection of activities necessary to ensure a method is properly installed in its selected environment. This will include the knowledge transfer activities such that the laboratory understand the critical control requirements of the method and the activities required to ensure the laboratory can meet these requirements e.g. purchasing of appropriate consumables such as columns, and reagents, ensuring reference standards are available, ensuring appropriate equipment is available and appropriate training is given to personnel.
Method Operational Qualification (MOQ) The collection of activities necessary to demonstrate that a method can meet its ATP. Experiments performed as part of the OQ exercise must be appropriate for the specific intended use as defined in the ATP. This may involve demonstrating the method has adequate precision and accuracy over the intended range of analyte concentrations for which it will be used.
Method Performance Qualification (MPQ)
The activities that demonstrate that a method performs as intended when used with the actual samples, facilities, equipment and personnel that will routinely operate the method.

About the AuthorsPhil Nethercote is head of the Analytical Centre of Excellence in GSK’s manufacturing division, and chairman of the GSK Analytical Standards Group. Since joining GSK in 1987 he has held a number of roles associated with new product introduction. He has a degree in Chemistry from Heriott-Watt University and a PhD in HPLC from Stirling University.

Phil Borman is a manager in Analytical Sciences, Chemical Development within GSK and is currently accountable for the application of Statistics globally within his department. Prior to his current role, Phil worked in both Chemical and Pharmaceutical Development. He has an M.S. in chemistry from the University of Manchester and an M.S. in industrial data modeling from De Montfort University in Leicester.
Tony Bennett is Project Leader for Laboratory Support in Quality Analytical Sciences, Existing Product Support, Global Manufacturing Supply at GSK.
Gregory P. Martin is President of Complectors Consulting, LLC, in Pottstown, Pennsylvania.
Pauline McGregor is Analytical Method Support Specialist for PMcG Consulting of Oakville, Ontario. She has over 20 years experience in validation, R&D and quality systems in the pharmaceutical industry.
References1. U.S. Food and Drug Administration (FDA). Draft Guidance for Industry
– Process Validation: General Principles and Practices. 2008.
2. FDA. “Pharmaceutical cGMPs for the 21st Century – A Risk-Based
Approach.” 2004.
3. Nasr, M. speaking at the 2005 AAPS Workshop on “Pharmaceutical
Quality Assessment - A Science and Risk-based CMC Approach
in the 21st Century.”
4. Borman, P., Nethercote, P., Chatfield, M., et al. Pharmaceutical
Technology, 31(10). 2007.
5. ICH Q8 (R2) – Pharmaceutical Development, November 2005.
6. Schweitzer, M., Pohl, M., Hanna-Brown, M., et al, Pharmaceutical
Technology, 34(2). 2010.
7. Ciurczak, E., ICH Guidances (Already) Show Their Age. www.
pharmamanufacturing.com/articles/2008/158.html

Cleaning Validation Principles

2010-12-30T20:37:00.001-08:00

Type: Classroom Training Course
Level: Intermediate
Level: Advanced

Date	Location	Country	Instructor(s)
9-10 November 2010	Annual Meeting Orlando, FL	USA	Becky Brewer
21-22 February 2011	Tampa Conference Tampa, FL	USA	Becky Brewer
9-10 March 2011	San Francisco, California	USA	Becky Brewer

Description

As cleaning technology and detection methodology advance, so do the challenges associated with establishing, managing, and maintaining a scientifically sound cleaning validation program. FDA's risk-based regulatory initiatives focus new attention on the risks of cross-contamination. The solution is to understand life cycle management techniques for an effective cleaning validation program.
This course will cover elements of a cleaning validation program from start to finish, exploring such concepts as the determination of residues to be targeted, selection of analytical and sampling methods, determination of appropriate limits in various pharmaceutical and biotechnology processes, and establishment of scientific rationales acceptable to regulatory inspectors. For mature cleaning validation programs, concepts such as understanding process control, capability, learning to effectively self-audit a cleaning validation program, and documentation will be essential takeaways.
This course contains knowledge related to the CPIP™ technical knowledge competency element Facilities and Equipment. For complete information concerning the knowledge elements or the CPIP Credential, please visit www.ispe-pcc.org.

Course Modules

Developing, Deploying and Maintaining
Regulatory Requirements
Fundamentals of Cleaning Validation
Master Plans
Equipment Characterization
SOP Development
Selecting Residues, Developing and Maintaining Limits
Methods Validation and Recovery Studies
Engineering Studies and Cycle Development
Creating Cleaning Validation Protocols
Collecting and Testing Validation Samples
Validation Reports

Take Back to Your Job

Identify and characterize potential residues including product, processing aids, cleaning agents, and adventitious agents
Apply appropriate analytical methodology for selected residues
Determine suitable sampling techniques and the selection of sampling locations that present a challenge for the cleaning process
Calculate residue limits that meet all necessary regulatory requirements
Create scientifically sound rationales, validation protocols, and reports
Manage the challenges of multi-product facilities in the establishment of limits, determination of validation strategies, and maintaining the validated state
Understand campaign-based production strategies for effective and scientifically sound validation
Differentiate the requirements for cleaning validation when using manual, semi-automatic, and automatic cleaning technologies
Determine scientific grouping or bracketing approaches
Comprehend the pitfalls inherent in cleaning after the production of biopharmaceutical and pharmaceutical products
Accomplish analytical method validation and recovery study requirements in cost-effective studies that provide the necessary assurance of an analytical system
Evaluate cleaning practices, limit calculations, scientific rationales, and validation documents through internal self-audits to ensure compliance with ever-changing regulatory needs
Practice hands-on exercises designed to reinforce core competencies and job-focused skills

Attendance Suggested For

Professionals responsible for all aspects of cleaning validation programs, including development, deployment, and maintenance
Quality assurance specialists, quality control technicians, regulatory affairs professionals, pharmacologists and toxicologists, validation scientists, and validation service personnel
Manufacturing supervisors, technical support personnel, and engineers responsible for evaluating cleaning systems, reviewing equipment, and supporting the cleaning validation program on the plant floor
All levels of management who need to understand the science of cleaning and cleaning validation including the aspects of residue selection, sampling method and analytical detection method validation, limits determination, and strategies for managing multi-product facilities

Continuing Education Units

ISPE will provide continuing education units (ISPE CEUs) for all North American seminars and courses, including educational programming at the ISPE Annual Meeting. CEUs are nationally recognized units of achievement designed for those individuals continuing their education in their chosen field or profession.
Delegates attending European seminars and courses will receive a Certificate of Attendance, as ISPE CEUs are currently not offered at European events. Verification of CEUs is based on attendance as well as satisfactory completion of all evaluation materials. Statements of credit will be sent via email within four weeks of evaluation materials. One hour of education programming equals 0.1 ISPE CEU credits.

THE APPLICABILITY OF CLEANING VALIDATION

2010-12-30T20:30:00.000-08:00

THE APPLICABILITY OF
CLEANING VALIDATION

Cleaning validation is primarily applicable to the cleaning of process manufacturing equipment in the pharmaceutical industry. Cleaning validation focuses on those cleaned equipment surfaces that, if inadequately cleaned, potentially could contaminate the product subsequently manufactured using that same equipment. This validation primarily covers product contact surfaces in the cleaned equipment (PIC/S, 2004), for these surfaces directly contact the next product. For clarification, the regulatory and scientific requirements for the cleaning of process equipment surfaces are different from those requirements for the cleaning of environmental cleanroom surfaces. While both involve aspects of cleaning, the focus of this book’s cleaning validation is product contact surfaces of process equipment.
This includes the interior surfaces of vessels, agitators, piping, hoses, pumps, and other items that directly contact the manufactured product and thus can transfer residues directly to the next product. There are some applications where indirect residue transfer may occur. I like to call these surfaces “indirect product contact” surfaces. Some examples of indirect transfer are clear. The reflux condenser in the organic synthesis of an active ingredient may not directly contact the next manufactured product; however, the

4 Cleaning Validation: Practial Compliance Solutions . . .
refluxing solvent does contact the condenser surfaces and potentially could carry residues from the condenser surfaces to the solvent containing the active ingredient.
A more controversial example of indirect transfer involves the interior surfaces of a lyophilizer (or freeze dryer). Although debate about transfer from lyophilizer surfaces may be controversial, there is a fairly clear regulatory expectation that cleaning validation will be performed for lyophilizers (FDA, 1993). It is possible that residues left behind (on shelves, for example) potentially could transfer by an airborne route to the manufactured product. Such a transfer has not been demonstrated in real life cases. Such a transfer is more likely to occur with lyophilizing of bulk product on trays than it is with lyophilizing of product in vials. One possible rationale for cleaning validation for lyophilizers is that most companies that lyophilize parenterals will sterilize the lyophilizer surfaces prior to use. The ostensible reason is that bioburden from the lyophilizer surfaces somehow could be transferred to the lyophilized product. If it is possible that bioburden from the surfaces could be transferred, though, is it also not likely that product could be transferred? One interesting feature of residues in lyophilizers is that adherent residues (which are generally most difficult to clean) are least likely to transfer via an airborne route, whereas loosely adherent residues (which are more likely to be removed in cleaning) are more likely to transfer via an airborne route. Whatever the situation, because the products manufactured in a lyophilizer are usually parenteral products, some companies have been asked by regulatory authorities to validate the cleaning of lyophilizers, while others have chosen to pursue cleaning validation for other reasons.
Other types of cleaning cannot be validated because of the frequency of performing the identical cleaning procedure (SOP). For example, for clinical trial materials or for drugs made infrequently (every year or two, for example), it is doubtful that the exact same cleaning SOP would be used three successive times in order to obtain three PQ (performance qualification) runs. While three runs no longer are the regulatory expectation for process validation purposes (FDA, 2004a; FDA, 2004b), in most cases companies still require a minimum of three PQ runs unless a different number is justified. In such cases, the cleaning process cannot be validated; however, it is

The Applicability of Cleaning Validation 5
still necessary to determine that the equipment is suitably cleaned for the manufacture of the next product. This calls for cleaning verification and involves performing tests similar to those done for the three PQ runs in cleaning validation, except that the tests are performed for each and every cleaning event. Although cleaning verification can be contrasted with cleaning validation, cleaning verification ordinarily should be defined in a cleaning validation policy or cleaning validation master plan.
Still other types of cleaning require neither validation nor verification. For example, cleaning of the outsides of tanks and the cleaning of walls and floors is required under GMPs. There should be SOPs defining those cleaning processes. However, those processes are not critical because the possibility of transfer to the product is remote, making validation unnecessary. When a significant possibility of transfer of residues from such surfaces to the next products exists, that situation should be rectified not by cleaning validation but rather by manufacturing controls. Furthermore, for extremely hazardous drug actives present on non-contact surfaces, there may be more of a concern related to personnel safety as compared to potential cross-contamination of the next manufactured product.
The applicability of cleaning validation should be written into a facility’s Cleaning Validation Master Plan to define clear situations that require validation, but also to permit professional judgment in cases that may require considered reflection.
The above chapter is based on a Cleaning Memo originally published in October, 2000.
www.pda.org/bookstore
6 Cleaning Validation: Practial Compliance Solutions . . .
REFERENCES
Food and Drug Administration (FDA). 1993. Guide to inspections of lyophilization of parenterals. July 1993. Washington, D.C.: U.S. Government Printing Office. Accessed 26 May 2006 at http://www.fda.gov/ora/inspect_ref/igs/lyophi.html
Food and Drug Administration (FDA). 2004a. FDA takes first step in recognizing the role of emerging technologies in the area of process validation. Mar. 17, 2004. Washington, D.C.: U.S. Government Printing Office. Accessed 26 May 2006 at http://www.fda.gov/cder/gmp/processvalidation.htm
Food and Drug Administration (FDA). 2004b. Sec. 490.100 process validation requirements for drug products and active pharmaceutical ingredients subject to pre-market approval (CPG 7132c.08). Revised Mar. 12, 2004. Washington, D.C.: U.S. Government Printing Office. Accessed 26 May 2006 at http://www.fda.gov/ora/compliance_ref/cpg/cpgdrg/cpg490-100.html
Pharmaceutical Inspection Convention Pharmaceutical Inspection Co-Operation Scheme (PIC/S). 2004. Recommendations on cleaning validation. Document PI 006-2. July 1, 2004. Geneva, Switzerland: PIC/S.

WHAT’S A CONTAMINANT?
Once at a training session at the FDA’s Basic Drug School, I was asked the question whether allowing a specified level of residue in a manufactured product (such as 0.001 of a therapeutic dose of a previous active) was, in fact, allowing manufacturers to produce and release drug products which were “contaminated.” My answer at the time was related to the fact that with newer analytical methods, we were able to measure residues at even lower levels, so that it was not feasible to specify that “no residues” of previous products appear in any other product. In giving this matter more thought, my answer would be slightly different. Rather than concede that any measured residue is a “contaminant,” I would now answer that question by stating that a contaminant is defined by both the presence of a “foreign” substance as well as the level of that substance in the drug.
This definition is related to the argument that “the dose makes the poison.” For example, selenium is considered a poison (causing selenosis) at doses of 500 micrograms, but is necessary in human diets at levels of about 50 micrograms. In fact, selenium is included in some vitamin and dietary supplement formulations at around 100 micrograms (NIH, 2004). This analogy doesn’t apply directly to residues in drugs because for the most part we are not considering substances that may have beneficial effects at extremely low levels.
However, consider situations where it is only certain levels of a given substance in a drug that render the substance to be classified

8 Cleaning Validation: Practial Compliance Solutions . . .
an “objectionable” contaminant. For example, bioburden in a non-sterile oral drug product can be present at certain levels, such as 75 CFU per gram, and not be considered objectionable. However, if those 75 CFU were E. coli, then one readily would conclude that the material was objectionably contaminated. It is both the nature of the substance and the level that are important.
This suggests that perhaps we should be more precise in our language as we discuss acceptable levels of residues. Thus, we should avoid phrases like “acceptable level of a given contaminant,” because in some cases it is the level that makes the “residue” a “contaminant.” Therefore, to say that a drug contains a residue of a previous drug at a given level is not to state that it is necessarily contaminated (or even adulterated). One way to look at this is to say that “a contaminant is an objectionable residue” (realizing, of course, that there may other types of contaminants).
This should not be used as an excuse to be sloppy in our cleaning efforts and say that any residue is okay as along as it is below the acceptance threshold. We should be conscientiously applying good manufacturing practices in our cleaning procedures so that any potentially contaminating residue is kept as low as practical. In a Human Drug CGMP Note, the FDA states that although equipment does not have to be absolutely clean as measured by the best available analytical technique, the equipment surfaces should be as clean as “reasonably achieved” by good cleaning procedures (FDA, 2001).
This is also not to be interpreted as saying that for any substance, some measurable amount may be acceptable. Consistent with the PIC/S cleaning validation guide (PIC/S, 2004), for certain allergens and cytotoxic substances, any residue should be below the limit of detection by the best available analytical technology. In such a case, one must still concede that a possibility exists that the drug will have a small, but not measurable (with current technology) residue of the allergen or cytotoxic material. If that unmeasured level of residue could still be objectionable, then in such a case it makes sense to use dedicated equipment.

Nor is it to ignore the fact that, with new information, levels that we regard acceptable today may become objectionable in the future. However, this is one of the tradeoffs we live with in trying to advance medical care.
The above chapter is based on a Cleaning Memo originally published in March, 2002.
What’s a Contaminant? 9

10 Cleaning Validation: Practial Compliance Solutions . . .

REFERENCES
Food and Drug Administration (FDA). 2001. Human drug CGMP notes. Second Quarter 2001. Washington, D.C.: U.S. Government Printing Office.
National Institutes of Health (NIH). 2004. Dietary supplement fact sheet: Selenium. Aug. 1, 2004. Bethesda, MD: Office of Dietary Supplements, NIH. Accessed 26 May 2006 at http://dietary-supplements.info.nih.gov/factsheets/selenium.asp
Pharmaceutical Inspection Convention Pharmaceutical Inspection Co-Operation Scheme (PIC/S). 2004. Recommendations on cleaning validation. Document PI 006-2. July 1, 2004. Geneva, Switzerland: PIC/S.

ADEQUATE
“DOCUMENTED EVIDENCE”
FOR CLEANING VALIDATION

A short definition of cleaning validation, consistent with a definition of process validation (FDA, 1987), is “documented evidence with a high degree of assurance that a cleaning process will consistently produce equipment and products meeting predetermined quality specifications.” In an internal audit or regulatory investigation, a key is reviewing that “documented evidence.” What could be included as part of that documented evidence?
One usually first thinks of the cleaning validation summary report. This is an important item. However, there is much more to the documented evidence than just this summary report. The consistency of the cleaning process is not demonstrated solely by the three (or whatever number is required) validation runs. It may be useful to think of the three validation runs as “confirming” the consistency of the cleaning process. The three validation runs are not experiments to determine if residues are acceptable. The experiments should be done earlier in the design of the cleaning SOP. At the point of cleaning validation, one should have a reasonable assurance that acceptable results will be the outcome. Therefore, other documents that could be considered part of the relevant “documented evidence” include the following:

12 Cleaning Validation: Practial Compliance Solutions . . .
• Cleaning validation master plan or high level policy
• Cleaning validation procedure
• Cleaning procedure or cleaning instruction
• Cleaning process development report or technology transfer report
• Cleaning validation protocol
• Analytical procedure
• Sampling procedure
• Report on rationale for selection of sampling locations
• Report on rationale for challenges (e.g., worst cases) to the cleaning process
• Analytical method validation
• Analytical/sampling method recovery
• Limits calculation report
• Deviation investigation report
• Training records
• Change control documents
• Monitoring records and/or trend reports
• Revalidation report and/or annual cleaning review report
Certainly under the new FDA investigation program (FDA, 2002), a key point to consider is the cleaning validation master plan or high level cleaning validation policy. This higher-level document—a practical necessity though not absolutely necessary—ties together most of the items listed above. One would question, for example, whether a cleaning process can still be considered validated (beyond the initial validation protocol) if it is not covered under a change control policy/procedure. Supporting the higher-level policy may be a more specific cleaning validation procedure document.
Another important document is the cleaning process procedure or instruction (or whatever the detailed cleaning process followed by the cleaning operator is called in a facility). One may have excellent validation data (for example, with all the swab and rinse

samples meeting the properly calculated acceptance criteria), but the cleaning process may be inadequately detailed and controlled such that there is no reasonable assurance that the cleaning process will produce the same data if carried out in the future. Appropriate design of the cleaning procedure is equally as important as appropriate design of the cleaning validation protocol.
The rationale for a cleaning process development report (which sometimes is called a technology transfer report) is twofold. One function is to provide future scientists in your company with a good rationale on how the cleaning process and the various parameters (cleaning agent, cleaning agent concentration, times, temperature, hold times, etc.) were selected. Furthermore, although such reports may not be critical to the validation investigation by regulatory authorities, those regulatory authorities may ask for this information. It is part of the emphasis of the FDA in asking pharmaceutical manufacturers to understand their manufacturing processes (FDA, 2004). A second reason is to provide assurance that the cleaning validation will be successful once the protocol is executed. As mentioned previously, the execution of the cleaning validation protocol should not be viewed as an experiment to test whether the cleaning process is effective; rather the “experiments” should be performed before the execution of the protocol in order to have a high degree of assurance that the cleaning process will be successfully validated when the cleaning validation protocol is carried out.
Other protocol related documents, such as the cleaning validation protocol itself, analytical procedure(s), sampling procedure(s), a report on the rationale for selection of sampling locations, a report on rationale for challenges (e.g., worst cases) to the cleaning process, analytical method validation, sampling/sampling method recovery, limits calculation report, training records, and any protocol deviation investigation report may exist as “stand alone” documents (e.g., analytical method validation), but some may also just be incorporated into the cleaning validation protocol (e.g., justification for sampling locations).
Other documents related to demonstrating consistency after initial validation is complete include the training records (particularly for any retraining on process clarifications and for operators
Adequate “Documented Evidence” for . . . 13

14 Cleaning Validation: Practial Compliance Solutions . . .

in manual cleaning processes), monitoring/trending after protocol execution, process-related deviations/investigations, change control, and revalidation.
The purpose of this chapter is not to proscribe certain ways to document cleaning validation but rather to consider all the evidence that can be part of the assurance of consistency of a cleaning process. This chapter should serve as a reminder that any of these documents may be requested as part of an audit or investigation of cleaning validation for a process or a facility.
The above chapter is based on a Cleaning Memo originally published in July, 2003.

REFERENCES

Food and Drug Administration (FDA). 1987. Guideline on general principles of process validation. May 1987. Accessed 26 May 2006 at http://www.fda.gov/cder/guidance/pv.htm
Food and Drug Administration (FDA). 2002. Compliance program guidance manual 7356.002, drug manufacturing inspections. Feb. 1, 2002. Washington, D.C.: U.S. Government Printing Office. Accessed 26 May 2006 at www.fda.gov/ora/cpgm/7356_002/7356-002FINAL.doc
Food and Drug Administration (FDA). 2004. Guideline for industry: PAT–a framework for innovative pharmaceutical development, manufacturing, and Quality Assurance. Sept. 2004. Washington, D.C.: U.S. Government Printing Office. Accessed 26 May 2006 at www.fda.gov/cder/guidance/6419fnl.pdf
Adequate “Documented Evidence” . . . 15

WATER QUALITY FOR

VALIDATED CLEANING PROCESSES

The quality of the water used for aqueous cleaning is critical for performance. This includes the water quality for any pre-rinse, for the washing step itself, and for any rinses. Quality includes chemical properties—pH, conductivity, hardness, Total Organic Carbon (TOC), etc.—and biological properties, including bioburden and endotoxin. Unfortunately, there are few regulatory guidelines that deal with this subject. (One guidance will be covered later.) However, there are a number of good scientific principles to apply. We’ll start with water quality for washing, then cover rinsing, and finally cover pre-rinsing.
Water for Washing
For the washing process, perhaps the most critical element to control is the water hardness (calcium and magnesium ions). Hardness ions are well known to affect the efficacy of cleaning of aqueous surfactant solutions (LeBlanc, 2000). If tap (potable) water is used for cleaning, hardness can be accounted for by using chelants in the cleaning formulation. It can also be a problem if the hardness in the water varies, either seasonally or by source. For example, some municipalities obtain their water both from surface waters and from deep wells. The deep-well water is more likely to have

18 Cleaning Validation: Practial Compliance Solutions . . .

an elevated degree of hardness. If a cleaning process were designed using the surface water, that cleaning process might not be effective if the deep-well water (with higher hardness) were used. A second concern with hardness ions in any tap water source is that, if alkaline cleaning agents are used (for example, those with potassium or sodium hydroxide), hardness ions may precipitate as calcium carbonate at high pHs. Depending on the conditions of precipitation, the result may cause a white residue on surfaces. That white residue may cause a surface to fail a “visually clean” criterion. This can be minimized by utilizing a cleaning agent with chelants, or by using an acidic post-rinse. The later approach is a common one and a carryover from cleaning processes in the dairy industry where the precipitation of “milk stone” (from the calcium in the milk) in the alkaline cleaning step is a routine feature.
Water for Rinsing
A general principle involving the manufacture of finished drugs utilizing water in the formulation is that the quality of the water for the final rinse should be at least as good as the quality of the water added in the next manufacturing process. For example, if a parenteral drug product is formulated with Water for Injection (WFI), then the final rinse of the previous cleaning process should be with WFI. If an oral drug product is formulated with Purified Water (PW), then the final rinse of the previous cleaning process should be with PW. The rationale for this is that any residues left behind from the final rinse are residues that would be added in the next product anyway. In this way, concerns about residues from the final rinse water itself are minimized. If water is used for rinsing, and the subsequently manufactured product does not have water in the manufacturing process, then additional information is required. For example, if the product is a non-sterile oral, solid dose product, PW clearly would be acceptable for a final rinse. If the aqueous cleaning process involves cleaning an active pharmaceutical ingredient (API) made by an organic synthesis route (in which no water is used in the synthesis), the most common approach is to use deionized water as the final rinse (such facilities rarely have a validated

Purified Water system). Of course, in that specific situation, some solvent rinse would be used after the water rinse to remove any water from the equipment, being that water would interfere with the organic synthesis.
One additional concern about the final rinse quality is that one also should be aware that using a lower quality water for the final rinse may leave behind mineral deposits, which in and of itself would not be a problem; however, those mineral deposits may be visible when the rinse water dries, and therefore would cause the equipment to fail any “visually clean” criterion.
Water for Pre-rinsing
In most cases, the quality of the water for pre-rinsing is the least critical of the three cases. After all, why be scrupulous about the quality of the water for this step when the greater issue is removing all the previous product? Water for pre-rinsing is solely used to flush residue out of the system prior to the washing step itself. Some companies will choose to recycle their water, and use for the pre-rinse the water from the previous final rinse (not from the initial post-rinses, for these will be highly contaminated with residues and cleaning agent). Choices of water quality to use for the pre-rinse sometimes are based on practical issues, such as using the same water as was used for the washing step.
Regulatory Guidance
One useful regulatory guidance on water quality for cleaning processes is the EMEA’s “Note for Guidance on Quality of Water for Pharmaceutical Use.” (EMEA, 2002). The relevant comments regarding water for cleaning are given in Table 5 of that document. That table is summarized as follows—
Water Quality for Validated Cleaning Processes
20 Cleaning Validation: Practial Compliance Solutions . . .
Note that this guidance does not address the quality of water used for the washing step.
Although not regulatory documents per se, FDA 483’s have been sent to some companies if they have used potable (tap) water for cleaning. However, the main issue was not the use of potable water but rather the lack of a monitoring program to measure and control the quality of the water. Such a monitoring program generally includes both chemical and microbiological quality of the water. Although records from testing at the water source by the municipality may help, it is best to have an onsite monitoring program in place in the individual pharmaceutical facility. This is a better measure of the water quality as it is used by the facility.

REFERENCES
European Agency for the Evaluation of Medicinal Products (EMEA). Note for guidance on quality of water for pharmaceutical use. May 2002. London, England: EMEA. Accessed 26 May 2006 at http://www.emea.eu.int/pdfs/human/qwp/015801en.pdf
LeBlanc, D. A. 2000. Validated cleaning technologies for pharmaceutical manufacturing. Englewood, CO: Interpharm Press.

CLEANING VALIDATION

2010-12-30T20:24:00.000-08:00

PRINCIPLE
1.1
Pharmaceutical products and active pharmaceutical ingredients (APIs) can be contaminated by other pharmaceutical products or APIs, by cleaning agents, by micro-organisms or by other material (e.g. air-borne particles, dust, lubricants, raw materials, intermediates, auxiliaries). In many cases, the same equipment may be used for processing different products. To avoid contamination of the following pharmaceutical product, adequate cleaning procedures are essential.
1.2
Cleaning procedures must strictly follow carefully established and validated methods of execution. This applies equally to the manufacture of pharmaceutical products and active pharmaceutical ingredients (APIs). In any case, manufacturing processes have to be designed and carried out in a way that contamination is reduced to an acceptable level.
1.3
Cleaning Validation is documented evidence that an approved cleaning procedure will provide equipment that is suitable for processing of pharmaceutical products or active pharmaceutical ingredients (APIs).
1.4
The objective of the Cleaning Validation is the confirmation of a reliable cleaning procedure so that the analytical monitoring may be omitted or reduced to a minimum in the routine phase.
2.
PURPOSE AND SCOPE
2.1
These guidance notes describe the validation of cleaning procedures for the removal of contaminants associated with the previous products, residues of cleaning agents as well as the control of potential microbial contaminants.
2.2
These guidance notes apply to the manufacture of pharmaceutical products (final dosage forms) and of active pharmaceutical ingredients (APIs).
3.
GENERAL
3.1
Normally only cleaning procedures for product contact surfaces of the equipment need to be validated. Consideration should be given to non-contact parts into which product may migrate. For example, seals, flanges, mixing shaft, fans of ovens, heating elements etc.
3.2
Cleaning procedures for product changeover in the case of marketed products should be fully validated.
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3.3
Generally in case of batch-to-batch production it is not necessary to clean after each batch. However, cleaning intervals and methods should be determined.
3.4
Several questions should be addressed when evaluating the cleaning process. For example:
-
At what point does a piece of equipment or system become clean?
-
What does ‘visually clean’ mean?
-
Does the equipment need to be scrubbed by hand?
-
What is accomplished by hand scrubbing rather than just a solvent wash?
-
How variable are manual cleaning processes from batch to batch and product to product?
-
What is the most appropriate solvent or detergent?
-
Are different cleaning processes required for different products in contact with a piece of equipment?
-
How many times need a cleaning process be applied to ensure adequate cleaning of each piece of equipment?
3.5
Cleaning procedures for products and processes, which are very similar, do not need to be individually validated. It is considered acceptable to select a representative range of similar products and processes concerned and to justify a validation program, which addresses the critical issues relating to the selected products and processes. A single validation study under consideration of the “worst case” can then be carried out which takes account of the relevant criteria. This practice is termed "Bracketing".
3.6
At least three consecutive applications of the cleaning procedure should be performed and shown to be successful in order to prove that the method is validated.
3.7
Raw materials sourced from different suppliers may have different physical properties and impurity profiles. Such differences should be considered when designing cleaning procedures, as the materials may behave differently.
3.8
Control of change to validated cleaning procedures is required. Re-validation should be considered under the following circumstances:
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3.8.1
Re-validation in cases of changes to equipment, products or processes; and
3.8.2
Periodic re-validation at defined intervals.
3.9
Manual methods should be reassessed at more frequent intervals than clean-in-place (CIP) systems.
3.10
It is usually not considered acceptable to "test until clean". This concept involves cleaning, sampling and testing, with repetition of this sequence until an acceptable residue limit is attained. For the system or equipment with a validated cleaning process, this practice of "test until clean" should not be required. The practice of "test until clean" is not considered to replace the need to validate cleaning procedures.
3.11
Products that simulate the physicochemical properties of the substance to be removed may be used instead of the substances themselves, where such substances are either toxic or hazardous.
4.
DOCUMENTATION
4.1
A Cleaning Validation Protocol is required laying down the procedure on how the cleaning process will be validated. It should include the following:
-
The objective of the validation process;
-
Responsibilities for performing and approving the validation study;
-
Description of the equipment to be used;
-
The interval between the end of production and the beginning of the cleaning procedures;
-
Cleaning procedures to be used for each product, each manufacturing system or each piece of equipment;
-
The number of cleaning cycles to be performed consecutively;
-
Any routine monitoring equipment;
-
Sampling procedures, including the rationale for why a certain sampling method is used;
-
Clearly defined sampling locations;
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Data on recovery studies where appropriate;
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Analytical methods including the limit of detection and the limit of quantitation of those methods;
-
The acceptance criteria, including the rationale for setting the specific limits;
-
Other products, processes, and equipment for which the planned validation is valid according to the “bracketing” concept; and
-
When Re-validation will be required.
4.2
The Cleaning Validation Protocol should be formally approved by the Plant Management, to ensure that aspects relating to the work defined in the protocol, for example personnel resources, are known and accepted by the management. Quality Assurance should be involved in the approval of protocols and reports.
4.3
A Final Validation Report should be prepared. The conclusions of this report should state if the cleaning process has been validated successfully. Limitations that apply to the use of the validated method should be defined (for example, the analytical limit at which cleanliness can be determined). The report should be approved by the Plant Management.
4.4
The cleaning process should be documented in an SOP.
4.5
Records should be kept of cleaning performed in such a way that the following information is readily available:
-
The area or piece of equipment cleaned;
-
The person who carried out the cleaning;
-
When the cleaning was carried out;
-
The SOP defining the cleaning process; and
-
The product, which was previously processed on the equipment being cleaned.
4.6
The cleaning record should be signed by the operator who performed the cleaning and by the person responsible for Production and should be reviewed by Quality Assurance.
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5.
PERSONNEL
5.1
Operators who perform cleaning routinely should be trained in the application of validated cleaning procedures. Training records should be available for all training carried out.
5.2
It is difficult to validate a manual, i.e. an inherently variable/cleaning procedure. Therefore, operators carrying out manual cleaning procedures should be supervised at regular intervals.
6.
EQUIPMENT
6.1
The design of the equipment should be carefully examined. Critical areas (those hardest to clean) should be identified, particularly in large systems that employ semi-automatic or fully automatic clean-in-place (CIP) systems.
6.2
Dedicated equipment should be used for products, which are difficult to remove (e.g. tarry or gummy residues in the bulk manufacturing), for equipment which is difficult to clean (e.g. bags for fluid bed dryers), or for products with a high safety risk (e.g. biologicals or products of high potency which may be difficult to detect below an acceptable limit).
7.
MICROBIOLOGICAL ASPECTS
7.1
The existence of conditions favorable to reproduction of micro-organisms (e.g. moisture, temperature, crevices and rough surfaces) and the time of storage should be considered. The aim should be to prevent excessive microbial contamination.
7.2
The period and when appropriate, conditions of storage of equipment before cleaning and the time between cleaning and equipment reuse, should form part of the validation of cleaning procedures. This is to provide confidence that routine cleaning and storage of equipment does not allow microbial proliferation.
7.3
In general, equipment should be stored dry, and under no circumstances should stagnant water be allowed to remain in equipment subsequent to cleaning operations.
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8.
SAMPLING
8.1
Samples should be drawn according to the Cleaning Validation Protocol.
8.2
There are two methods of sampling that are considered to be acceptable, direct surface sampling (swab method) and indirect sampling (use of rinse solutions). A combination of the two methods is generally the most desirable, particularly in circumstances where accessibility of equipment parts can mitigate against direct surface sampling.
A.
Direct Surface Sampling
(i) The suitability of the material to be used for sampling and of the sampling medium should be determined. The ability to recover samples accurately may be affected by the choice of sampling material. It is important to ensure that the sampling medium and solvent are satisfactory and can be readily used.
B.
Rinse Samples
(i)
Rinse samples allow sampling of a large surface area. In addition, inaccessible areas of equipment that cannot be routinely disassembled can be evaluated. However, consideration should be given to the solubility of the contaminant.
(ii)
A direct measurement of the product residue or contaminant in the relevant solvent should be made when rinse samples are used to validate the cleaning process.
9.
DETERGENTS
9.1
The efficiency of cleaning procedures for the removal of detergent residues should be evaluated. Acceptable limits should be defined for levels of detergent after cleaning. Ideally, there should be no residues detected. The possibility of detergent breakdown should be considered when validating cleaning procedures.
9.2
The composition of detergents should be known to the manufacturer. If such information is not available, alternative detergents should be selected whose composition can be defined. As a guide, food regulations may be consulted. The manufacturer should ensure that he is notified by the detergent supplier of any critical changes in the formulation of the detergent.
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10.
ANALYTICAL METHODS
10.1
The analytical methods should be validated before the Cleaning Validation Study is carried out.
10.2
The analytical methods used to detect residuals or contaminants should be specific for the substance to be assayed and provide a sensitivity that reflects the level of cleanliness determined to be acceptable by the company.
10.3
The analytical methods should be challenged in combination with the sampling methods used, to show that the contaminants can be recovered from the equipment surface and to show the level of recovery as well as the consistency of recovery. This is necessary before any conclusions can be made based on the sample results. A negative result may also be the result of poor sampling techniques.
11.
ESTABLISHMENT OF LIMITS
11.1
The pharmaceutical company's rationale for selecting limits for product residues should be logically based on a consideration of the materials involved and their therapeutic dose. The limits should be practical, achievable and verifiable.
11.2
The approach for setting limits can be:
-
product specific Cleaning Validation for all products,
-
grouping into product families and choosing a ‘worst-case’ product,
-
grouping into groups of risk (e.g. very soluble products, similar potency, highly toxic products, difficult to detect).
11.3
Carry-over of product residues should meet defined criteria. For example, the most stringent of the following three criteria:
(a)
No more than 0.1%of the normal therapeutic dose of any product will appear in the maximum daily dose of the following product,
(b)
No more than 10ppm of any product will appear in another product,
(c)
No quantity of residue should be visible on the equipment after cleaning procedures are performed. Spiking studies should determine the concentration at which most active ingredients are visible,
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(d)
For certain allergenic ingredients, penicillins, cephalosporins or potent steroids and cytotoxics, the limit should be below the limit of detection by best available analytical methods. In practice this may mean that dedicated plants are used for these products.
11.4
One cannot ensure that the contaminate will be uniformly distributed throughout the system. It is also an invalid conclusion to make the assumption that a residual contaminant would be worn off the equipment surface uniformly or that the contamination might only occur at the beginning of the batch.
11.5
In establishing residual limits, it may not be adequate to focus only on the principal reactant since chemical variations (active decomposition materials) may be more difficult to remove.
12.
REFERENCE
12.1 PIC/S document, PI 006-3: Recommendations on Validation Master Plan, Installation and Operational Qualification, Non-Sterile Process Validation, Cleaning Validation.

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